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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Contribution of Angiotensin II to Alcohol-Induced Pancreatic Fibrosis in Rats

Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (T.U., M.F., E.G., F.I., B.U.B., G.E.A.); Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan (T.U., I.I., Y.Y.); and Department of Pharmacology and Toxicology and the James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (G.E.A.)

The mechanisms by which alcohol causes pancreatic fibrosis remain unknown. Recent studies have demonstrated that angiotensin II contributes to the development of fibrosis in liver, kidney, and heart injury. Here, the effects of angiotensin-converting enzyme inhibitor (captopril) and angiotensin II receptor antagonist (losartan) on alcohol-induced pancreatic fibrosis were examined in an intragastric ethanol-feeding model. Male rats were fed a high-fat liquid diet with either ethanol (16–20 g/kg/day) or isocaloric maltose-dextrin (control) for 4 weeks. Subgroups daily received captopril (60 mg/kg/day), losartan (3 mg/kg/day), or no additional agent included in liquid diets. Mean urine alcohol concentrations in all groups fed ethanol were more than 270 mg/dl and not significantly different. Dietary alcohol caused diffuse gland atrophy and interlobular and intralobular fibrosis with mild structural distortion in the pancreas, an effect that was blunted by captopril or losartan treatment. Alcohol also increased the number of -smooth muscle actin-positive cells and transforming growth factor- mRNA expression in the pancreas. These increases were blunted significantly by captopril or losartan treatment. These data suggest that angiotensin II contributes to the development of chronic alcohol-induced pancreatic fibrosis through its stimulation of transforming growth factor- expression.

Address correspondence to: Dr. Gavin E. Arteel, Department of Pharmacology and Toxicology, 1307 Research Tower, HSC, University of Louisville School of Medicine, Louisville, KY 40292. E-mail: gavin.arteel{at}louisville.edu